Grange, Laura J, Reynolds, John J, Ullah, Farid, Isidor, Bertrand, Shearer, Robert F, Latypova, Xenia, Baxley, Ryan M, Oliver, Antony W, Ganesh, Anil, Cooke, Sophie L, Jhujh, Satpal S, McNee, Gavin S, Hollingworth, Robert, Higgs, Martin R, Natsume, Toyoaki, Khan, Tahir, Martos-Moreno, Gabriel Á., Chupp, Sharon, Mathew, Christopher G., Parry, David, Simpson, Michael A., Nahavandi, Nahid, Yüksel, Zafer, Drasdo, Mojgan, Kron, Anja, Vogt, Petra, Jonasson, Annemarie, Seth, Saad Ahmed, Gonzaga-Jauregui, Claudia, Brigatti, Karlla W, Stegmann, Alexander P A, Kanemaki, Masato, Josifova, Dragana, Uchiyama, Yuri, Oh, Yukiko, Morimoto, Akira, Osaka, Hitoshi, Ammous, Zineb, Argente, Jesús, Matsumoto, Naomichi, Stumpel, Constance T.R.M., Taylor, Alexander M.R., Jackson, Andrew P., Bielinsky, Anja-Katrin, Mailand, Niels, Le Caignec, Cedric, Davis, Erica E. and Stewart, Grant S. (2022). Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy. Nature Communications, 13 (1),
Abstract
Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.
| Publication DOI: | https://doi.org/10.1038/s41467-022-34349-8 |
|---|---|
| Divisions: | College of Health & Life Sciences > School of Biosciences College of Health & Life Sciences |
| Additional Information: | Copyright © The Author(s), 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. |
| Uncontrolled Keywords: | Humans,Cell Cycle Proteins/genetics,Microcephaly/genetics,DNA Repair/genetics,Chromosomes/metabolism,Genomic Instability,DNA-Binding Proteins/metabolism,Ubiquitin-Protein Ligases/metabolism,Chromosomal Proteins, Non-Histone/metabolism |
| Publication ISSN: | 2041-1723 |
| Last Modified: | 23 Dec 2024 08:51 |
| Date Deposited: | 20 Jun 2023 14:58 |
| Full Text Link: | |
| Related URLs: |
https://www.nat ... 467-022-34349-8
(Publisher URL) |
PURE Output Type: | Article |
| Published Date: | 2022-11-04 |
| Accepted Date: | 2022-10-21 |
| Authors: |
Grange, Laura J
Reynolds, John J ( 
0000-0001-8690-5828)
Ullah, Farid Isidor, Bertrand Shearer, Robert F Latypova, Xenia Baxley, Ryan M Oliver, Antony W Ganesh, Anil Cooke, Sophie L Jhujh, Satpal S McNee, Gavin S Hollingworth, Robert Higgs, Martin R Natsume, Toyoaki Khan, Tahir Martos-Moreno, Gabriel Á. Chupp, Sharon Mathew, Christopher G. Parry, David Simpson, Michael A. Nahavandi, Nahid Yüksel, Zafer Drasdo, Mojgan Kron, Anja Vogt, Petra Jonasson, Annemarie Seth, Saad Ahmed Gonzaga-Jauregui, Claudia Brigatti, Karlla W Stegmann, Alexander P A Kanemaki, Masato Josifova, Dragana Uchiyama, Yuri Oh, Yukiko Morimoto, Akira Osaka, Hitoshi Ammous, Zineb Argente, Jesús Matsumoto, Naomichi Stumpel, Constance T.R.M. Taylor, Alexander M.R. Jackson, Andrew P. Bielinsky, Anja-Katrin Mailand, Niels Le Caignec, Cedric Davis, Erica E. Stewart, Grant S. |
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